Approximately 10% of all treated patients with hemophilia A (Factor VIII:C deficiency) develop inhibitory antibodies to Factor VIII:C. This event is unpredictable and, when it occurs, further effective replacement therapy is often precluded. At the present time, no single approach to management has received universal acceptance as being efficacious. The overall objective of the studies proposed is to: 1) determine the pathogenetic mechanisms responsible for the development of inhibitors to Factor VIII:C and 2) develop new approaches to the treatment of such patients. A hemophilic dog breeding program has been established and a simple reproducible model of bleeding, amenable to Factor VIII:C therapy correction, developed. Some of the treated animals have developed potent Factor VIII:C inhibitors and thus provide a precise animal model of the human condition. The specific aims of the proposal are to maintain hemophilic animals with an without inhibitor development and characterize both the inhibitors and the functional domain on the Factor VIII:C molecule recognized by them. In order to do this, individual inhibitors will be isolated and uses as immunogens in hybridoma systems in order to raise specific anti-idiotype antibodies. These antibodies will be used to catalogue the natural history of individual antibodies in any one animal and in other animals exposed to the same antigen (Factor VIII:C) challenge. In addition, the use of these reagents in blocking assays between Factor VIII:C and individual anti-Factor VIII:C antibodies should allow the determination of functional significance of individual antibodies. The availability of a precise canine in clinical studies. In further studies, it is intended to use anti-idiotype antibodies directed against antibodies shown to be of functional significance to therapeutically modify the inhibition of infused Factor VIII:C replacement. This will be achieved either by direct infusion of such monoclonal antibodies or by employing immunodepletion techniques by extracorporeal perfusion of immobilized anti-idiotype antibody.